Soft tissue sarcoma presents therapeutic challenges in multimodality management. Excellent local tumor control can usually be obtained by surgery in conjunction with radiotherapy. However, this does not translate into acceptable overall survival rates in that approximately 50% of soft tissue sarcoma patients ultimately fail, usually due to pulmonary metastases. Such metastases, if not resectable, are presently only marginally controlled by markedly toxic chemotherapy regimens. The soft tissue sarcoma problem is further complicated by two different and non-interconvertible staging systems, a persistent 40% discordancy rate regarding microscopic determinations of histopathologic diagnosis and tumor grade even among expert sarcoma pathologists, a lack of information about molecular determinants of sarcoma proliferation and metastasis, and multicenter clinical trials that have had at least a one decade-long accrual period due to the relative rarity of this disease, resulting in an inability to implement new therapeutic approaches to this disease for at least fifteen years. This research application seeks to address these problems by proposing an innovative single institution prospective randomized trial that is linked via an integrated clinical-molecular prospective database to an already established bioresource facility containing a tissue bank, short term culture explants and cell lines, and relevant paraffin-embedded tissue blocks. These tools will be used to address the following five specific aims: 1. Does the deletion of preoperative radiotherapy impair local tumor control for soft tissue sat-coma patients who have responded to neoadjuvant chemotherapy? 2. Does preresection hyperthermic isolated limb perfusion (HILP) offer more effective local tumor control than preoperative radiotherapy for soft tissue sat-coma patients who have not responded to neoadjuvant chemotherapy? 3. Can molecular staging criteria be developed that provide accurate prognosis for survival and/or predict responsiveness to anticipated therapy where the biopsy materials are obtained by fine needle aspiration? 4. Based on an improved understanding of the mechanisms underlying HILP-mediated tumor cytotoxicity, is it possible to develop improved biochemotherapy regimens for this therapeutic application? 5. Using bioresources derived from patients enrolled in the clinical trial, is it possible to elucidate the molecular mechanisms underlying MDM2 oncogene and MTS1 tumor suppressor gene participation in soft tissue sarcoma proliferation and dissemination?